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C/EBPß regulates multiple IL-1ß-induced human astrocyte inflammatory genes

Abstract

BACKGROUND: CCAAT enhancer binding protein (C/EBP)beta regulates gene expression in multiple organ systems and cell types, including astrocytes in the central nervous system (CNS). Inflammatory stimuli, interleukin (IL)-1beta, tumor necrosis factor-alpha, human immunodeficiency virus (HIV)-1 and lipopolysaccharide induce astrocyte C/EBPbeta expression. C/EBPbeta is detectable in brains of Alzheimer's disease (AD), Parkinson disease (PD) and HIV-1-associated dementia (HAD) patients, yet little is known about how C/EBPbeta contributes to astrocyte gene regulation during neuroinflammation. METHODS: The expression of 92 human inflammation genes was compared between IL-1beta-treated primary human astrocytes and astrocytes transfected with C/EBPbeta-specific small interfering (si)RNA prior to IL-1beta treatment for 12 h. Transcripts altered by >two-fold compared to control were subjected to one-way analysis of variance and Newman-Keuls post-test for multiple comparisons. Expression of two genes, COX-2 and BDKRB2, was further confirmed in additional human astrocyte donors. Astrocytes were treated with mitogen activated protein kinase-selective inhibitors, then with IL-1beta for 12 or 24 h followed by cyclooxygenase-2 (COX-2) and bradykinin receptor B2 (BDKRB2) expression analyses. RESULTS: IL-1beta altered expression of 29 of 92 human inflammation genes by at least two-fold in primary human astrocytes in 12 h. C/EBPbeta knockdown affected expression of 17 out of 29 IL-1beta-regulated genes by at >|25|%. Two genes relevant to neuroinflammation, COX-2 and BDKRB2, were robustly decreased and increased, respectively, in response to C/EBPbeta knockdown, and expression was confirmed in two additional donors. COX-2 and BDKRB2 mRNA remained altered in siRNA-transfected astrocytes at 12, 24 or 72 h. Inhibiting p38 kinase (p38K) activation blocked IL-1beta-induced astrocyte COX-2 mRNA and protein expression, but not IL-1beta-induced astrocyte BDKRB2 expression. Inhibiting extracellular regulated kinase (ERK)1/2 activation blocked IL-1beta-induced BDKRB2 mRNA expression while increasing COX-2 expression. CONCLUSION: These data support an essential role for IL-1beta in the CNS, and identify new C/EBPbeta functions in astrocytes. Additionally, this work suggests p38K and ERK1/2 pathways may regulate gene expression in a complementary manner to fine-tune the IL-1beta-mediated astrocyte inflammatory response. Delineating a role for C/EBPbeta, and other involved transcription factors in human astrocyte inflammatory response, may lead to effective therapies for AD, PD, HAD and other neurological disorders. METHODS: The expression of 92 human inflammation genes was compared between IL-1beta-treated primary human astrocytes and astrocytes transfected with C/EBPbeta-specific small interfering (si)RNA prior to IL-1beta treatment for 12 h. Transcripts altered by >two-fold compared to control were subjected to one-way analysis of variance and Newman-Keuls post-test for multiple comparisons. Expression of two genes, COX-2 and BDKRB2, was further confirmed in additional human astrocyte donors. Astrocytes were treated with mitogen activated protein kinase-selective inhibitors, then with IL-1beta for 12 or 24 h followed by cyclooxygenase-2 (COX-2) and bradykinin receptor B2 (BDKRB2) expression analyses. RESULTS: IL-1beta altered expression of 29 of 92 human inflammation genes by at least two-fold in primary human astrocytes in 12 h. C/EBPbeta knockdown affected expression of 17 out of 29 IL-1beta-regulated genes by at >|25|%. Two genes relevant to neuroinflammation, COX-2 and BDKRB2, were robustly decreased and increased, respectively, in response to C/EBPbeta knockdown, and expression was confirmed in two additional donors. COX-2 and BDKRB2 mRNA remained altered in siRNA-transfected astrocytes at 12, 24 or 72 h. Inhibiting p38 kinase (p38K) activation blocked IL-1beta-induced astrocyte COX-2 mRNA and protein expression, but not IL-1beta-induced astrocyte BDKRB2 expression. Inhibiting extracellular regulated kinase (ERK)1/2 activation blocked IL-1beta-induced BDKRB2 mRNA expression while increasing COX-2 expression. CONCLUSION: These data support an essential role for IL-1beta in the CNS, and identify new C/EBPbeta functions in astrocytes. Additionally, this work suggests p38K and ERK1/2 pathways may regulate gene expression in a complementary manner to fine-tune the IL-1beta-mediated astrocyte inflammatory response. Delineating a role for C/EBPbeta, and other involved transcription factors in human astrocyte inflammatory response, may lead to effective therapies for AD, PD, HAD and other neurological disorders.

PMID: 22818222
[PubMed - as supplied by publisher]

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